Abstract

Gangliosides are a family of sialic acid-containing glycosphingolipids that are enriched in the nervous system. They are located in the outer leaflet of the plasma membrane within lipid rafts and are thought to be involved in numerous cellular events, including proliferation, differentiation, migration and neurite outgrowth. Gangliosides have also been shown to have neuroprotective actions and have been considered as candidates for the treatment of several neurodegenerative disorders.
In this thesis, the role of gangliosides in glial proliferation, migration and differentiation as well as the regeneration of the olfactory system and myelination were studied using mice lacking enzymes involved in ganglioside biosynthesis. Regeneration of the olfactory system in ganglioside knockout mice was similar to that of wild-type mice. However, proliferation of olfactory ensheathing cells grown on collagen and the migration of Schwann cells grown on laminin or collagen was increased in Sia T -/- mice, which lack b-series gangliosides but have increased levels of a-series gangliosides. These findings suggest that complex gangliosides modulate glial cell function to some extent. However, since the effects observed were subtle, it is possible that simpler gangliosides are able to compensate for the lack of complex gangliosides.
Axonal density and myelination were unaffected in ganglioside knockout mice. However, the localisation of sodium channels at the node of Ranvier and potassium channels at juxtaparanode was retarded in GalNAc T -/- mice lacking all complex gangliosides, suggesting that complex gangliosides modulate the formation of nodes of Ranvier. In addition, GalNAc T -/- mice had significantly lower numbers of NG2 positive early oligodendrocyte progenitors compared to wild-type and Sia T -/- mice, suggesting that complex gangliosides may affect early progenitor differentiation, proliferation or survival.